Guanine, illustrated below, is one the five heterocyclic bases commonly found in DNA and RNA. Guanine is a particularly difficult base to work with because coupling of the base with electrophilic reagents usually results in N.sup.7 /N.sup.9 isomeric mixtures that are frequently difficult to separate and result in decreased yields. ##STR1##
An acyclic nucleoside is one that contains a non-cyclic carbohydrate or carbohydrate-type group attached to the purine or pyrimidine base. Two guanine-containing acyclic nucleosides that are currently used therapeutically for the treatment of viruses are 9-(2-hydroxyethoxymethyl)-guanine (acyclovir) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine ("DHPG").
Acyclovir, illustrated below, is administered therapeutically for the treatment of herpes simplex virus (types 1 and 2) and varicella zoster virus (herpes zoster and chicken pox). H. J. Schaeffer. et al. Nature (London). 1978, 272, 583; Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press (1989). ##STR2##
Discovery of the potent activity of acyclovir led to many efforts to synthesize the compound. A number of schemes have been proposed or used. One method involves the condensation of silylated guanine with 2-benzoxyethoxymethyl chloride in the presence of Bu.sub.4 NF as a catalyst to give exclusively the N.sup.9 -substituted product. G. H. Hakimelahi. et al. Helv. Chim. 1989, 72, 1495.
Chen et al., J. China Pharm. Univ. 1992, 23(1), 43, prepared acyclovir by reacting diacetylguanine with dioxolane in the presence of p-toluenesulfonic acid. The product was a syrup containing a mixture of N.sup.9 /N.sup.7 -isomers in which the ratio of N.sup.9 /N.sup.7 -isomers was about 3/2 in favor of the N.sup.9 -isomer. Contrary to the article, however, the present inventors did not observe any significant amount of N.sup.9 -isomer precipitating from this syrup after treatment with chloroform.
Matsumoto, et al., have studied the effect of solvent, acid catalyst and reaction temperature on yield of the alkylation of diacetylguanine with 2-oxo-1,4-butanediol diacetate ("dioxolane diacetate") to produce N.sup.2,O-diacetylacyclovir. H. Matsumoto. et al. Chem. Pharm. Bull. 1988, 36 (3), 1153. Of the acid catalysts tested (p-toluenesulfonic acid, sulfanilic acid, p-nitrobenzenesulfonic acid, 2,4-dinitrobenzene sulfonic acid, iron(II) sulfate, and zinc chloride), Matsumoto reported that p-toluenesulfonic acid and sulfanilic acid exhibited the highest catalytic activity. The Matsumoto method provides a mixture of N.sup.9 - and N.sup.7 -substituted compounds which had to be separated. Matsumoto deprotected N.sup.2,O-diacetylacyclovir with methanol saturated with ammonia, to provide an overall yield of acyclovir of 43%. O-Acetylacyclovir was obtained when methanolic methoxide was used, and N.sup.2 -acetylacyclovir was obtained when aqueous ammonium hydroxide was used. Matsumoto reported that DMSO was the solvent of choice for the reaction.
Diacetylguanine, which has been used as an intermediate in the production of acyclovir, has been prepared using several methods. Guanine has been acetylated using acetic anhydride in N,N-dimethylacetamide to give diacetylguanine in 90.5% yield. M. J. Robins. Can.J.Chem. 1987, 65, 1436. This reaction produces a product which is grey in color due to the high reaction temperature used (160.degree. C. for 7 hours).
Guanine has also been acetylated in acetic anhydride and acetic acid to give different products depending on the workup conditions. H. Matsumoto. et al. Chem.Pharm.Bull. 1988, 36 (3), 1153. For example, after the reaction mixture becomes an almost clear solution, if solvents are removed by distillation, only diacetyl guanine is obtained in 95% yield. However, the addition of water at 60.degree. C. followed by stirring at room temperature overnight produces N.sup.2 -acetylguanine in 94.4% yield. If the reaction mixture is merely cooled down, a mixture of mono- and di-acetylguanine is produced.
2-Amino-6-chloropurine has been acetylated in acetic anhydride in the presence of phosphoric acid. E. M. Acton, R. H. Iwamoto, Synthetic Procedures in Nucleic Acid Chemistry. 1968, 1, 25. The reaction produced di- and tri-acetylated products in forty minutes. However, the acetylation of guanine under these conditions required more catalyst (8.4%) and a longer reaction time (3 hours) than 2-amino-6-chloropurine. During the reaction, the acetylated guanine became deep brown, and the coloration was difficult to remove.
9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine (DHPG), illustrated below, has been approved by the U.S. Food and Drug Administration for use as an antiviral agent for human cytomegalovirus infections in AIDS patients. ##STR3##
Martin et al. and Ogilvie et al. have reported the synthesis of DHPG via the reaction of N-acetylguanine (Scheme 1) or 6-chloroguanine with 1,3-dibenzyloxy-2-chloromethoxypropane. J. C. Martin et al., 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: A New Potent and Selective Antiherpes Agent. J. Med. Chem. 1983, 26(5), 759-761; K. K. Ogilvie et al. Biologically active acyclonucleoside analogues. II. The Synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (BIOLF-62), Can. J. Chem. 1982, 60, 3005-3010. ##STR4##
The reaction of N-acetylguanine and 1,3-dibenzyloxy-2-chloromethoxypropane in the presence of tributyl ammonium iodide provided a yield of 28% of the N.sup.7 -isomer and 28% of the N.sup.9 -isomer of the acetylated, dibenzylated product. It was also observed by the present inventors that, despite comments to the contrary in the article, the benzyl protected condensation intermediate produced in Scheme 1 was difficult to deprotect. Accordingly, it would be desirable to develop a procedure which does not require the use of this type of protecting group, and which provides a higher yield of the N.sup.9 -isomeric product.
6-Chloroguanine is not a preferred reagent for the industrial scale synthesis of DHPG because it is relatively expensive.
An alternative method for the production of DHPG was reported by A. K. Field et al. and W. I. Ashton et al. Field, A. K. et al., 9{[2-Hydroxyl-1-(hydroxymethyl)ethoxy]methyl}guanine: A selective inhibitor of herpes group virus replication. Proc. Natl. Acad. Sci.: USA, 1983, 80 4139-4143; Ashton, W. T. et al, European patent 0165164 A1, 1985. This procedure, illustrated in Scheme 2, involves the reaction of 1,3-diacetoxy-2-acetoxymethoxy propane with diacetylguanine and toluenesulfonic acid. ##STR5##
The key intermediate used in Scheme 2, namely, 2-acetoxymethoxy-1,3-diacetoxypropane, has been produced as illustrated in Scheme 3 (Field) or Scheme 4 (Ashton). ##STR6##
The syntheses shown in Schemes 3 and 4 are difficult to carry out, and they produce the desired product as a mixture of isomers which can only be separated with great difficulty using HPLC. This is not a commercially viable route for the production of these compounds.
Accordingly, it would be desirable to provide a method for the synthesis of acyclic guanine nucleosides, and in particular, acyclovir and DHPG, which can be carried out effectively on an industrial scale.
It is an object of the present invention to provide an improved method for the industrial production of acyclic purine nucleosides, and a particular, acyclic guanine nucleosides.
It is another object of the present invention to provide an improved method for the industrial preparation of acyclovir.
It is a further object of the present invention to provide an improved method for the industrial production of DHPG.